The neuroendocrine system is known to be associated with brain aging. Age-dependent loss of hippocampal neurons is well documented in rat, monkey and human suggesting universal mechanisms in hippocampal aging. Life-long exposure to glucocorticoids results in the loss of hippocampal neurons in rats. The objective of these studies is to test the hypothesis that a loss of regulatory control over glucocorticoid action results in hippocampal aging and neurodegeneration. Experiments have been designed to test the working hypothesis in the hippocampus of aging rats because (A) this area us a jet site of action of glucocorticoids, (B) neuronal cell loss in this brain region occurs during aging and the loss is modulated by glucocorticoids, and (C) I have cloned a glucocorticoid-regulated gene found in hippocampal neurons which can serve as a marker of glucocorticoid action. We propose that the mechanism of the neuron loss is due to loss of regulation of key glucocorticoid regulated genes. Transgenic mice expressing the antisense strand of the mineralocorticoid receptor will be used to directly test the glucocorticoid hypothesis. In addition, these studies will explore the general use of transgenic animals to target specific gene expression to be used with models of learning and memory as well as age-related changes and neurodegeneration. The results of these studies will enhance our understanding of he functional integration between glucocorticoids and hippocampal aging and neurodegeneration.